Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that is caused by mutations in PKD genes. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a class of medications that mimic the actions of the hormone GLP-1, conferring beneficial effects on weight management and other metabolic conditions. However, whether GLP-1RA plays a kidney-protective action in ADPKD remains unknown. In this study, we define the role and mechanisms of one of the most popular GLP-1RA agonists, Semaglutide, in ADPKD. We show that the expression of GLP-1R is decreased in Pkd1 mutant renal epithelial cells and kidneys. Treatment with Semaglutide delays cyst growth in aggressive and long-lasting Pkd1 mutant mouse models. Treatment with Semaglutide (1) decreases glucose uptake, ATP generation, and glycolysis, (2) deactivates PKD-associated signaling pathways, including Rb, S6, and Stat3, resulting in a decrease in cell proliferation, (3) deactivates NF-kB signaling pathways, resulting in a decrease in the expression of cytokines and the recruitment of macrophages, (4) normalizes mitochondrial morphology and function, (5) induces Pkd1 mutant renal epithelial cell death, (6) induces ketosis characterized by an increase in serum level of beta-hydroxybutyrate (BHB) and the activation of AMPK, and (7) alleviates renal fibrosis through deactivation of TGF-b signaling in Pkd1 mutant mouse kidneys. This study highlights the potential of GLP-1R agonists as a novel therapeutic strategy for ADPKD treatment.